Conventional anti-inflammatory steroids, such as cortisone, hydrocortisone, prednisone, methylprednisolone, etc., are generally poorly water soluble and therefore not suited for intravenous administration. Several types of soluble C-21 derivatives of such steroids have been disclosed in the patent literature including dicarboxylic acid hemiesters, sulfobenzoates, sulfopropionates, sulfates, phosphates, and aminoalkanoyloxy derivatives. While solubilization can generally be attained quite readily using a variety of such pro-moieties, most of the aforementioned derivatives possess other disadvantages limiting their utility as water soluble prodrugs. (The term "prodrug" denotes a derivative of an active drug which is converted after administration back to the active drug. The "pro-moiety" referred to in this application is the fragment attached to the steroid via an ester linkage and removed by ester hydrolysis in vivo.) A major problem with many common derivatives is their solution instability. Dicarboxylic acid hemiesters such as succinate esters, for example, are marketed commercially as lyophilized powders for reconstitution prior to injection due to their solution instability.
Numerous publications are available on the stability of 21-esters of corticosteroids. A partial listing of these articles and their content is given below:
Factors Influencing Solvolysis of Corticosteroid 21-Phosphate Esters, G. L. Flynn and D. J. Lamb, J. Pharm. Sci. 59, 1433 (1970).
Stability of Corticosteroid Hemiesters of Dicarboxylic Acids, E. R. Garrett, J. Pharm. Sci., 51, 445 (1962); E. R. Garrett, J. Med. Pharm. Chem., 5, 112 (1962); B. D. Anderson and V. Taphouse, J. Pharm. Sci., 70, 181 (1981); R. Yamamoto, S. Fujisawa, and M. Kawamura, Yakugaku Zasshi, 91, 855 (1971).
Stability of Corticosteroid 21-Aminoalkylcarboxylates, M. Kawamura, R. Yamamoto, and S. Fujisawa, Yakugaku Zasshi, 91, 863 (1971).
Stability of Corticosteroid 21-Sulfobenzoates and 21-Sulfate, M. Kawamura, R. Yamamoto, and S. Fujisawa, Yakugaku Zasshi, 91, 871 (1971).
Certain derivatives which do appear to exhibit sufficient solution stability may not be readily converted to the active drug in vivo. The 21-sulfate ester of hydrocortisone, for example, exhibits good solution stability but is inactive in mice. Other derivatives may possess the requisite solubility, stability, and bioconversion, but exhibit other disadvantages. Several undesirable features of phosphate esters, for example, are apparent: (1) Phosphate esters are often difficult to purify and are frequently very hygroscopic. (2) The stability of phosphate esters is optimum above pH 7 where other modes of drug degradation may be a problem. Glass surfaces are also more likely to delaminate in alkaline conditions resulting in particulate problems. (3) Precipitation of free corticosteroid due to the limited amount of hydrolysis which does occur may limit product shelf-life. Solubilization of free corticosteroid by the intact prodrug is a desirable feature which phosphate esters exhibit to only a limited extent.
The present invention provides a class of compounds which overcome these problems, providing novel solution stable prodrugs of corticosteroids.